COMPARISON OF CLINICAL AND REAL-LIFE TRiaLS OF THE EFFECTIVENESS OF ANTI-VEGF THERAPY FOR age-related macular degeneration

In recent years, the approaches to assessing results have been changed in both clinical and real life trials with the introduction of Aflibercept to clinical practice. In most countries, ranibizumab and aflibercept are licensed for the treatment of neovascular age-related macular degeneration (AMD). The assessment of the treatment effectiveness and economic cost was carried out within the frame of different clinical trials with existing strict limitations. The article reviews the results of studies conducted in various clinical trials. Data on long-term follow-up after anti-VEGF therapy for neovascular AMD form, especially in real-life studies, are limited. In the framework of the HORIZON study, representing an extended four-year follow-up of ANCHOR and MARINA patients, the gradual reduction in visual acuity has been revealed in the first 2 years of follow-up period. The re-examination of 10 % of patients from the initial ANCHOR and MARINA studies has been described in the SEVEN-UP study; herewith the decrement in visual activity has been detected after 7 years on the beginning of the clinical studies examination (loss of 8.6 letters against initial letter). The data obtained can not be directly transmitted into routine clinical practice, due to the patients’ inclusion and exclusion Criterion presence, protocols for the introduction of drugs, etc. A study of the therapy’s effectiveness and economic cost in real time allows optimizing the treatment of patients with neovascular AMD.

age-related macular degeneration, choroidal neovascularization, clinical trials, anti-VEGF therapy, ranibizumab, aflibercept

1. Abedi F., Wickremasinghe S., Richardson A.J., Islam A.F., Guymer R.H., Baird P.N. Genetic influences on the outcome of anti-vascular endothelial growth factor treatment in neovascular age-related macular degeneration // Ophthalmology. 2013. 120. (8). 1641-1648.

2. Abedi F., Wickremasinghe S., Richardson A.J., Makalic E., Schmidt D.F., Sandhu S.S. et al. Variants in the VEGFA gene and treatment outcome after anti-VEGF treatment for neovascular age-related macular degeneration // Ophthalmology. 2013. 120. (1). 115-121.

3. Aflibercept solution for injection for treating wet age-related macular degeneration. NICE technology appraisal guidance 294, guidanceniceorguk/ta294. 2013. ISBN 978-1-4731-0234-7.

4. Beykin G., Grunin M., Averbukh E., Banin E., Hemo Y., Chowers I. Bevacizumab treatment for neovascular age-related macular degeneration in the setting of a clinic: “real life” long-term outcome // BMC Ophthalmol. 2015. 15. 39.

5. Brantley M.A., Jr, Fang A.M., King J.M., Tewari A., Kymes S.M., Shiels A. Association of complement factor H and LOC387715 genotypes with response of exudative age-related macular degeneration to intravitreal bevacizumab // Ophthalmology. 2007. 114. (12). 2168-2173.

6. Brown D.M., Kaiser P.K., Michels M., Soubrane G., Heier J.S., Kim R.Y. et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration // N. Engl. J. Med. 2006. 355. (14). 1432-1444.

7. Brown D.M., Michels M., Kaiser P.K., Heier J.S., Sy J.P., Ianchulev T. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: Two-year results of the ANCHOR study // Ophthalmology. 2009. 116. (1). 57-65.

8. Calabresi P.A., Giovannoni G., Confavreux C., Galetta S.L., Havrdova E., Hutchinson M., Kappos L., Miller D.H., O’Connor P.W., Phillips J.T., Polman C.H., Radue E.W., Rudick R.A., Stuart W.H., Lublin F.D., Wajgt A., Weinstock-Guttman B., Wynn D.R., Lynn F., Panzara M.A. The incidence and significance of anti-natalizumab antibodies: results from AFFIRM and SENTINEL // Neurology. 2007. 69. (14). 1391-1403.

9. Chowers I., Cohen Y., Goldenberg-Cohen N., Vicuna-Kojchen J., Lichtinger A., Weinstein O., Pollack A., Axer-Siegel R., Hemo I., Averbukh E., Banin E., Meir T., Lederman M. Association of complement factor H Y402H polymorphism with phenotype of neovascular age related macular degeneration in Israel // Mol. Vis. 2008. 14. 1829-1834.

10. Ding X., Patel M., Chan C.C. Molecular pathology of age-related macular degeneration // Prog. Retin. Eye Res. 2009. 281. 1-18.

11. Eghoj M.S., Sorensen T.L. Tachyphylaxis during treatment of exudative age-related macular degeneration with ranibizumab // Br. J. Ophthalmol. 2012. 96. (1). 21-23.

12. Forooghian F., Cukras C., Meyerle C.B., Chew E.Y., Wong W.T. Tachyphylaxis after intravitreal bevacizumab for exudative age-related macular degeneration // Retina. 2009. 29. (6). 723-731.

13. Fox E.J., Vartanian T.K., Zamvil S.S. The immunogenicity of disease-modifying therapies for multiple sclerosis: clinical implications for neurologists // Neurologist. 2007. 13. (6). 355-362.

14. Fritsche L.G., Chen W., Schu M., Yaspan B.L., Yu Y., Thorleifsson G., Zack D.J., Arakawa S., Cipriani V., Ripke S. et al. Seven new loci associated with age-related macular degeneration // Nat. Genet. 2013. 45. (4). 433-439.

15. Hagstrom S.A., Ying G.S., Pauer G.J., Sturgill-Short G.M., Huang J., Callanan D.G., Kim I.K., Klein M.L., Maguire M.G., Martin D.F. Pharmacogenetics for genes associated with age-related macular degeneration in the Comparison of AMD Treatments Trials (CATT) // Ophthalmology. 2013. 120. (3). 593-599.

16. Heier J.S., Brown D.M., Chong V., Korobelnik J.F., Kaiser P.K., Nguyen Q.D., Kirchhof B., Ho A., Ogura Y., Yancopoulos G.D., Stahl N., Vitti R., Berliner A.J., Soo Y., Anderesi M., Groetzbach G., Sommerauer B., Sandbrink R., Simader C., Schmidt-Erfurth U. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration // Ophthalmology. 2012. 119. (12). 2537-2548.

17. Holz F.G., Amoaku W., Donate J., Guymer R.H., Kellner U., Schlingemann R.O., Weichselberger A., Staurenghi G. Safety and efficacy of a flexible dosing regimen of ranibizumab in neovascular age-related macular degeneration: the SUSTAIN study // Ophthalmology. 2011. 118. (4). 663-671.

18. Imai D., Mori K., Horie-Inoue K., Gehlbach P.L., Awata T., Inoue S., Yoneya S. CFH, VEGF, and PEDF genotypes and the response to intravitreous injection of bevacizumab for the treatment of age-related macular degeneration // J. Ocul. Biol. Dis. Inform. 2010. 3. (2). 53-59.

19. Investigators I.S., Chakravarthy U., Harding S.P., Rogers C.A., Downes S.M., Lotery A.J., Wordsworth S., Reeves B.C. Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from the IVAN randomized trial // Ophthalmology. 2012. 119. (7). 1399-1411.

20. Johnston S.S., Wilson K., Huang A., Smith D., Varker H., Turpcu A. Retrospective analysis of first-line anti-vascular endothelial growth factor treatment patterns in wet age-related macular degeneration // Adv. Ther. 2013. 30. (12). 1111-1127.

21. Kanoff J., Miller J. Pharmacogenetics of the treatment response of age-related macular degeneration with ranibizumab and bevacizumab // Semin. Ophthalmol. 2013. 28. (5-6). 355-356.

22. Kruger Falk M., Kemp H., Sorensen T.L. Four-year treatment results of neovascular age-related macular degeneration with ranibizumab and causes for discontinuation of treatment // Am. J. Ophthalmol. 2013. 155. (1). 89-95.

23. Lotery A.J., Gibson J., Cree A.J., Downes S.M., Harding S.P., Rogers C.A., Reeves B.C., Ennis S., Chakravarthy U. Pharmacogenetic associations with vascular endothelial growth factor inhibition in participants with neovascular age-related macular degeneration in the IVAN study // Ophthalmology. 2013. 120. (12). 2637-2643.

24. Martin D.F., Maguire M.G., Fine S.L., Ying G.S., Jaffe G.J., Grunwald J.E., Toth C., Redford M., Ferris F.L. 3rd. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results // Ophthalmology. 2012. 119. (7). 1388-1398.

25. Mitchell P. A systematic review of the efficacy and safety outcomes of anti-VEGF agents used for treating neovascular age-related macular degeneration: comparison of ranibizumab and bevacizumab // Curr. Med. Res. Opin. 2011. 27. (7). 1465-1475.

26. Pushpoth S., Sykakis E., Merchant K., Browning A.C., Gupta R., Talks S.J. Measuring the benefit of 4 years of intravitreal ranibizumab treatment for neovascular age-related macular degeneration // Br. J. Ophthalmol. 2012. 96. (12). 1469-1473.

27. Raftery J., Clegg A., Jones J., Tan S.C., Lotery A. Ranibizumab (Lucentis) versus bevacizumab (Avastin): modelling cost effectiveness // Br. J. Ophthalmol. 2007. 91. (9). 1244-1246.

28. Rasmussen A., Bloch S.B., Fuchs J., Hansen L.H., Larsen M., Lacour M., Lund-Andersen H., Sander B. A 4-year longitudinal study of 555 patients treated with ranibizumab for neovascular age-related macular degeneration // Ophthalmology. 2013. 120. (12). 2630-2636.

29. Rofagha S., Bhisitkul R.B., Boyer D.S., Sadda S.R., Zhang K. Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: a multicenter cohort study (SEVEN-UP) // Ophthalmology. 2013. 120. (11). 2292-2299.

30. Rosenfeld P.J., Brown D.M., Heier J.S., Boyer D.S., Kaiser P.K., Chung C.Y., Kim R.Y. Ranibizumab for neovascular age-related macular degeneration // N. Engl. J. Med. 2006. 355. (14). 1419-1431.

31. Schaal S., Kaplan H.J., Tezel T.H. Is there tachyphylaxis to intravitreal anti-vascular endothelial growth factor pharmacotherapy in age-related macular degeneration? // Ophthalmology. 2008. 115. (12). 2199-2205.

32. Schmid M.K., Bachmann L.M., Fas L., Kessels A.G., Job O.M., Thiel M.A. Efficacy and adverse events of aflibercept, ranibizumab and bevacizumab in age-related macular degeneration: a trade-off analysis // Br. J. Ophthalmol. 2015. 99. (2). 141-146.

33. Schmid M.K., Reich O., Faes L., Boehni S.C., Bittner M., Howell J.P., Thiel M.A., Signorell A., Bachmann L.M. Comparison of outcomes and costs of ranibizumab and aflibercept treatment in real-life // PLoS One. 2015. 10. (8). e0135050.

34. Schmidt-Erfurth U., Kaiser P.K., Korobelnik J.F., Brown D.M., Chong V., Nguyen Q.D., Ho A.C., Ogura Y., Simader C., Jaffe G.J., Slakter J.S., Yancopoulos G.D., Stahl N., Vitti R., Berliner A.J., Soo Y., Anderesi M., Sowade O., Zeitz O., Norenberg C., Sandbrink R., Heier J.S. Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the VIEW studies // Ophthalmology. 2013. 121. (1). 193-201.

35. Seddon J.M., Yu Y., Miller E.C., Reynolds R., Tan P.L., Gowrisankar S., Goldstein J.I., Triebwasser M., Anderson H.E., Zerbib J., Kavanagh D., Souied E., Katsanis N., Daly M.J., Atkinson J.P., Raychaudhuri S. Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration // Nat. Genet. 2013. 45. (11). 1366-1370.

36. Silva R., Axer-Siegel R., Eldem B., Guymer R., Kirchhof B., Papp A., Seres A., Gekkieva M., Nieweg A., Pilz S. The SECURE study: long-term safety of ranibizumab 0.5 mg in neovascular age-related macular degeneration // Ophthalmology. 2013. 120. (1). 130-139.

37. Singer M.A., Awh C.C., Sadda S., Freeman W.R., Antoszyk A.N., Wong P., Tuomi L. HORIZON: an open-label extension trial of ranibizumab for choroidal neovascularization secondary to age-related macular degeneration // Ophthalmology. 2012. 119. (6). 1175-1183.

38. Svenson M., Geborek P., Saxne T., Bendtzen K. Monitoring patients treated with anti-TNF-alpha biopharmaceuticals: assessing serum infliximab and anti-infliximab antibodies // Rheumatology. 2007. 46. (12). 1828-1834.

39. Tian J., Qin X., Fang K., Chen Q., Hou J., Li J., Yu W., Chen D., Hu Y., Li X. Association of genetic polymorphisms with response to bevacizumab for neovascular age-related macular degeneration in the Chinese population // Pharmacogenomics. 2012. 13. (7). 779-787.

40. Vedula S.S., Krzystolik M.G. Antiangiogenic therapy with anti-vascular endothelial growth factor modalities for neovascular age-related macular degeneration // Cochrane Database Syst. Rev. 2008. (2). CD005139

41. Zhao L., Grob S., Avery R., Kimura A., Pieramici D., Lee J., Rabena M., Ortiz S., Quach J., Cao G., Luo H., Zhang M., Pei M., Song Y., Tornambe P., Goldbaum M., Ferreyra H., Kozak I., Zhang K. Common variant in VEGFA and response to anti-VEGF therapy for neovascular age-related macular degeneration // Curr. Mol. Med. 2013. 13. (6). 929-934.